ROR gamma (RORy) modulators

ABSTRACT

The present invention relates to compounds according to Formula I: or a pharmaceutically acceptable salt thereof. The compounds can be used as inhibitors of RORy and are useful for the treatment of RORy mediated diseases such as autoimmune and inflammatory diseases.

The retinoic-acid-receptor-related orphan receptor γt (RORγt) acts as amaster regulator of the development of T_(H)17 cells, but also as acritical component in non-T_(H)17 IL-17 producing cells, such as forexample γδ T-cells. The ROR gene family is part of the nuclear hormonereceptor superfamily, and consists of three members (RORα, RORβ, andRORγ). Each gene is expressed in different isoforms, differing foremostin their N-terminal sequence. Two isoforms of RORγ have been identified:RORγ1 and RORγ2 (also known as RORγt). The term RORγ is used here todescribe both RORγ1 and/or RORγ2.

The present invention relates to novel RORγ modulator compoundscontaining a 4-[2-(4-sulfonylphenyl)acetamido]benzamide scaffold, topharmaceutical compositions comprising the same and to the use of saidcompounds for the treatment of RORγ-mediated diseases or conditions, inparticular autoimmune diseases and inflammatory diseases.

The present invention relates to compounds according to Formula I

or a pharmaceutically acceptable salt thereof wherein:

-   -   A₁-A₈ are N or CR₁-CR₈, respectively, with the proviso that no        more than two of the four positions A in A₁-A₄ can be        simultaneously N and that no more than two of the four positions        A in A₅-A₈ can be simultaneously N;    -   R₁-R₈ are independently H, halogen, amino, C(1-3)alkoxy,        (di)C(1-3)alkylamino or C(1-6)alkyl;    -   R₉ is C(1-6)alkyl;    -   R₁₀ and R₁₁ are independently H, F, methyl, ethyl, hydroxy or        methoxy or R₁₀ and R₁₁ together is carbonyl, all alkyl groups,        if present, optionally being substituted with one or more F;    -   R₁₂ is H or C(1-6)alkyl;    -   R₁₃ is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl,        C(2-5)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl,        C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)hetero-aryl or        C(1-9)heteroarylC(1-3)alkyl, all groups optionally substituted        with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy,        C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;    -   R₁₄ is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl,        C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl,        C(2-5)heterocycloalkylC(1-3)alkyl, C(6-10)aryl,        C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl or        C(1-9)heteroarylC(1-3)alkyl, all groups optionally substituted        with one or more halogen, amino, hydroxy, cyano, C(1-3)alkoxy,        C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;    -   or R₁₃ and R₁₄ are fused and form a ring having 5 to 7 atoms by        joining R₁₃ being C(1-6)alkyl or C(2-6)alkenyl with an        independent substituent within the definition of R₁₄, all groups        optionally substituted with one or more halogen, amino, hydroxy,        cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino        or C(1-3)alkyl.

The term C(1-6)alkyl as used herein means a branched or unbranched alkylgroup having 1-6 carbon atoms, for example methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms mayoptionally be substituted with one or more halogen.

The term C(1-3)alkyl as used herein means an alkyl group having 1-3carbon atoms, i.e. methyl, ethyl, propyl or isopropyl. All carbon atomsmay optionally be substituted with one or more halogen.

The term C(2-6)alkenyl as used herein means a branched or unbranchedalkenyl group having 2-6 carbon atoms, for example 4-hexenyl,but-2-enyl, 1-methylenepropyl, 2-propenyl (allyl) and ethenyl (vinyl).All carbon atoms may optionally be substituted with one or more halogen.

The term C(6-10)aryl as used herein means an aromatic hydrocarbon grouphaving 6-10 carbon atoms, for example phenyl or naphthyl. All carbonatoms may optionally be substituted with one or more halogen.

The term C(6-10)arylC(1-3)alkyl as used herein means an C(6-10)arylgroup attached to a C(1-3)alkyl group, both with the same meaning aspreviously defined.

The term C(6)aryl as used herein means an aromatic hydrocarbon grouphaving 6 carbon atoms, i.e. phenyl. All carbon atoms may optionally besubstituted with one or more halogen.

The term C(6)arylC(1-3)alkyl as used herein means an C(6)aryl groupattached to a C(1-3)alkyl group, both with the same meaning aspreviously defined.

The term heteroatom as used herein refers to a nitrogen, sulfur oroxygen atom.

The term amino as used herein refers to an NH₂ group.

The term C(1-9)heteroaryl as used herein means an aromatic group having1-9 carbon atoms and 1-4 heteroatoms, which may be attached via anitrogen atom if feasible, or a carbon atom. Examples includeimidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, furyl, pyrazolyl,isoxazolyl, tetrazolyl, oxazol, thiazol and quinolyl. All carbon atomsmay optionally be substituted with one or more halogen or methyl.

The term C(1-9)heteroarylC(1-3)alkyl as used herein means anC(1-9)heteroaryl group attached to a C(1-3)alkyl group, both with thesame meaning as previously defined.

The term C(1-5)heteroaryl as used herein means an aromatic group having1-5 carbon atoms and 1-4 heteroatoms, which may be attached via anitrogen atom if feasible, or a carbon atom. Examples includeimidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, furyl, pyrazolyl,isoxazolyl, and tetrazolyl. All carbon atoms may optionally besubstituted with one or more halogen or methyl.

The term C(1-5)heteroarylC(1-3)alkyl as used herein means anC(1-5)heteroaryl group attached to a C(1-3)alkyl group, both with thesame meaning as previously defined.

The term C(3-6)cycloalkyl as used herein means a saturated cyclichydrocarbon having 3-6 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. All carbon atoms may optionally besubstituted with one or more halogen or methyl.

The term C(3-6)cycloalkylC(1-3)alkyl as used herein means anC(3-6)cycloalkyl group attached to an C(1-3)alkyl group, both with thesame meaning as previously defined. An example is cyclopropylmethyl.

The term C(2-5)heterocycloalkyl as used herein means a saturated cyclichydrocarbon having 2-5 carbon atoms and 1-3 heteroatoms, which may beattached via a nitrogen atom if feasible, or a carbon atom. Examplesinclude piperazinyl, pyrazolidyl, piperidinyl, morpholinyl, oxolanyl andpyrrolidinyl. All carbon atoms may optionally be substituted with one ormore halogen or methyl.

The term C(4)heterocycloalkyl as used herein means a saturated cyclichydrocarbon having 4 carbon atoms and 1-3 heteroatoms, which may beattached via a nitrogen atom if feasible, or a carbon atom. Examplesinclude piperazinyl, oxolanyl and pyrrolidinyl. All carbon atoms mayoptionally be substituted with one or more halogen or methyl.

The term C(2-5)heterocycloalkylC(1-3)alkyl as used herein means anC(2-5)heterocycloalkyl group attached to an C(1-3)alkyl group, both withthe same meaning as previously defined.

The term C(4)heterocycloalkylC(1-3)alkyl as used herein means anC(4)heterocycloalkyl group attached to a C(1-3)alkyl group, both withthe same meaning as previously defined.

The term (di)C(1-3)alkylamino as used herein means an amino group, whichis monosubstituted or disubstituted with a C(1-3)alkyl group, the latterhaving the same meaning as previously defined.

The term C(1-3)alkoxy means an alkoxy group having 1-3 carbon atoms, thealkyl moiety being branched or unbranched. All carbon atoms areoptionally substituted with one or more F.

The term C(1-3)alkoxycarbonyl means a carbonyl group substituted with aC(1-3)alkoxy, the latter having the same meaning as previously defined.

The term halogen as used herein means Cl or F.

In the above definitions with multifunctional groups, the attachmentpoint is at the last group.

When, in the definition of a substituent, is indicated that “all of thealkyl groups” of said substituent are optionally substituted, this alsoincludes the alkyl moiety of an alkoxy group.

The term “substituted” means that one or more hydrogens on thedesignated atom/atoms is/are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. “Stable compound” or “stable structure” is defined asa compound or structure that is sufficiently robust to survive isolationto a useful degree of purity from a reaction mixture, and formulationinto an efficacious therapeutic agent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term pharmaceutically acceptable salt represents those salts whichare, within the scope of medical judgment, suitable for use in contactfor the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. They may be obtained during the final isolationand purification of the compounds of the invention, or separately byreacting the free base function with a suitable mineral acid such ashydrochloric acid, phosphoric acid, or sulfuric acid, or with an organicacid such as for example ascorbic acid, citric acid, tartaric acid,lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid,succinic acid, propionic acid, acetic acid, methanesulfonic acid, andthe like. The acid function can be reacted with an organic or a mineralbase, like sodium hydroxide, potassium hydroxide or lithium hydroxide.

In one embodiment the invention relates to a compound according toFormula I wherein:

-   -   A₁-A₄ are respectively CR₁-CR₄;    -   or A₁ and A₄ are respectively CR₁ and CR₄ and A₂ or A₃ is N, the        remaining position A being CR₂ or CR₃;    -   A₅-A₈ are respectively CR₅-CR₈;    -   or A₅ and A₈ are respectively CR₁ and CR₄ and A₆ or A₇ is N, the        remaining position A being CR₆ or CR₇;    -   R₁-R₄ are independently H, halogen or C(1-6)alkyl;    -   R₅-R₈ are independently H;    -   R₉ is C(1-3)alkyl;    -   R₁₀ and R₁₁ are independently H;    -   R₁₂ is H;    -   R₁₃ is C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl,        C(2-5)heterocycloalkylC(1-3)alkyl, C(6-10)aryl,        C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl or        C(1-9)heteroarylC(1-3)alkyl, all groups optionally substituted        with one or more C(1-3)alkyl;    -   R₁₄ is C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl,        C(2-5)heterocycloalkyl, C(6-10)aryl, or C(6-10)arylC(1-3)alkyl,        all groups optionally substituted with one or more halogen,        hydroxy or C(1-3)alkyl;    -   or R₁₃ and R₁₄ are fused and form a ring having 5 to 7 atoms by        joining R₁₃ being C(1-6)alkyl or C(2-6)alkenyl with an        independent substituent within the definition of R₁₄ being        C(6-10)aryl or C(6-10)arylC(1-3)alkyl.

In another embodiment the invention relates to a compound according toFormula I wherein:

-   -   A₁-A₄ are respectively CR₁-CR₄;    -   or A₁ and A₄ are respectively CR₁ and CR₄ and A₂ or A₃ is N, the        remaining position A being CR₂ or CR₃;    -   A₅-A₈ are respectively CR₅-CR₈;    -   or A₅ and A₈ are respectively CR₁ and CR₄ and A₆ or A₇ is N, the        remaining position A being CR₆ or CR₇; R₁-R₄ are independently        H, CI, F or methyl;    -   R₅-R₈ are independently H;    -   R₉ is ethyl;    -   R₁₀ and R₁₁ are independently H;    -   R₁₂ is H;    -   R₁₃ is cyclobutyl, cyclopropylmethyl, oxolanylpropanyl, phenyl,        benzyl, oxazolyl, pyrazolyl, thiadiazolyl, thiazolyl, pyridinyl,        oxazolylmethyl or furanylmethyl, all groups optionally        substituted with one or more methyl;    -   R₁₄ is methyl, ethyl, tertbutyl, hydroxypropyl, propyl,        cyclopropyl, cyclobutyl, oxolanyl, phenyl or benzyl, all groups        optionally substituted with one or more F, or methyl; or R₁₃ and        R₁₄ are fused and form a 1,2,3,4-tetrahydroquinoline,        phenylpyrrolidine or phenylpiperidine.

In one embodiment the invention relates to a compound according toFormula I wherein:

-   -   A₁-A₄ are respectively CR₁-CR₄;    -   A₅ and A₈ are respectively CR₅ and CR₈;    -   A₆ or A₇ is N, the remaining position A being CR₆ or CR₇;    -   R₁-R₄ are independently H or halogen;    -   R₅-R₈ are independently H;    -   R₉ is C(1-3)alkyl;    -   R₁₀ and R₁₁ are independently H;    -   R₁₂ is H;    -   R₁₃ is C(6-10)aryl;    -   and R₁₄ is C(1-6)alkyl.

In another embodiment the invention relates to a compound according toFormula I wherein:

-   -   A₁-A₄ are respectively CR₁-CR₄;    -   A₅ and A₈ are respectively CR₅ and CR₈;    -   A₆ or A₇ is N, the remaining position A being CR₆ or CR₇;    -   R₁-R₄ are independently H, Cl or F;    -   R₅-R₈ are independently H;    -   R₉ is ethyl;    -   R₁₀ and R₁₁ are independently H;    -   R₁₂ is H;    -   R₁₃ is phenyl;    -   and R₁₄ is ethyl or tertbutyl.

In one embodiment the invention relates to a compound according toFormula I wherein all positions A in A₁-A₄ are CR₁-CR₄.

In another embodiment the invention relates to a compound according toFormula I wherein all positions A in A₅-A₈ are CR₅-CR₈.

In another embodiment the invention relates to a compound according toFormula I wherein all of the positions A in A₁-A₈ are carbon.

In another embodiment the invention relates to a compound according toFormula I wherein one of the positions A in A₁-A₈ is N, the remainingpositions A being carbon. In another embodiment the invention relates toa compound according to Formula I wherein either position A₁ or A₂ is Nand the remaining positions A in A₁-A₈ are CR₁-CR₈.

In another embodiment the invention relates to a compound according toFormula I wherein either position A₆ or A₇ is N and the remainingpositions A in A₁-A₈ are CR₁-CR₈. In another embodiment the inventionrelates to a compound according to Formula I wherein R₁-R₈ areindependently H, halogen, methoxy or methyl.

In yet another embodiment the invention relates to a compound accordingto Formula I wherein R₁-R₈ are independently H, halogen or methyl.

In another embodiment the invention relates to a compound according toFormula I wherein all positions R in R₁-R₄ are H.

In another embodiment the invention relates to a compound according toFormula I wherein all positions R in R₁-R₄ are halogen or methyl.

In yet another embodiment the invention relates to a compound accordingto Formula I wherein R₈ is methyl and all positions R in R₅-R₇ are H.

In another embodiment the invention relates to a compound according toFormula I wherein all positions R in R₅-R₈ are H.

In again another embodiment the invention relates to a compoundaccording to Formula I wherein all positions R in R₁-R₈ are H.

In one embodiment the invention also relates to a compound according toFormula I wherein R₉ is C(1-3)alkyl.

In another embodiment the invention also relates to a compound accordingto Formula I wherein R₉ is ethyl.

In one embodiment the invention relates to a compound according toFormula I wherein R₁₀ and R₁₁ are independently H, methyl or hydroxyl.

In another embodiment the invention relates to a compound according toFormula I wherein R₁₀ and R₁₁ are both H.

The invention also relates to a compound according to Formula I whereinR₁₂ is H or C(1-3)alkyl.

In another embodiment the invention relates to a compound according toFormula I wherein R₁₂ is H.

In one embodiment the invention relates to a compound according toFormula I wherein R₁₃ is C(3-6)cycloalkyl, C(3)cycloalkylC(1-3)alkyl,C(2-5)heterocycloalkyl, C(4)heterocycloalkylC(1-3)alkyl, C(6)aryl,C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl,all groups optionally substituted with one or more halogen, amino,hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylaminoor C(1-3)alkyl.

In another embodiment the invention relates to a compound according toFormula I wherein R₁₃ is C(3-6)cycloalkyl, C(3)cycloalkylC(1-3)alkyl,C(4)heterocycloalkylC(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl,C(1-5)heteroaryl, or C(1-5)heteroarylC(1-3)alkyl, all groups optionallysubstituted with one or more C(1-3)alkyl.

In yet another embodiment the invention relates to a compound accordingto Formula I wherein R₁₄ is H, C(1-6)alkyl, C(2-6)alkenyl,C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(4)heterocycloalkyl,C(2-5)heterocycloalkylC(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl,C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl, all groups optionallysubstituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl.

In yet another embodiment the invention relates to a compound accordingto Formula I wherein R₁₄ is C(1-6)alkyl, C(3-6)cycloalkyl,C(4)heterocycloalkyl, C(6)aryl or C(6)arylC(1-3)alkyl, all groupsoptionally substituted with one or more halogen, hydroxy or C(1-3)alkyl.

In another embodiment the invention relates to a compound according toFormula I wherein R₁₄ is H or C(1-6)alkyl, all alkyl chains optionallysubstituted with one or more halogen. In yet another embodiment theinvention relates to a compound according to Formula I wherein R₁₃ andR₁₄ are fused and form a ring having 5 to 7 atoms by joining R₁₃ beingC(1-6)alkyl or C(2-6)alkenyl with an independent R₁₄ substituentselected from C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl,C(2-5)heterocycloalkyl, C(2-5)heterocycloalkyl-C(1-3)alkyl, C(6)aryl,C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl,all groups optionally substituted with one or more halogen, amino,hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylaminoor C(1-3)alkyl.

In again another embodiment the invention relates to a compoundaccording to Formula I wherein R₁₃ and R₁₄ are fused and form a ringhaving 5 to 7 atoms by joining R₁₃ being propyl with R₁₄ selected fromC(1-6)alkyl, C(2-6)alkenyl, C(2-5)heterocycloalkyl,C(2-5)heterocycloalkylC(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl,C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl, with all groupsoptionally substituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl.

In again another embodiment the invention relates to a compoundaccording to Formula I wherein R₁₃ and R₁₄ are fused and form a ringhaving 5 to 7 atoms by joining R₁₃ being propyl with R₁₄ selected fromC(6)aryl or C(6)arylC(1-3)alkyl. The invention also relates to thosecompounds wherein all specific definitions for A₁ through A₈, R₁ throughR₁₄, and all substituent groups in the various aspects of the inventionsdefined here above occur in any combination within the definition of thecompound of Formula I.

In another aspect the invention relates to compounds of Formula I, whichhave a pIC50 of 5 or higher. In yet another aspect the invention relatesto compounds according to Formula I with a pIC50 of more than 6. In yetanother aspect the invention relates to compounds according to Formula Iwith a pIC50 of more than 7. In yet another aspect the invention relatesto compounds according to Formula I with a pIC50 of more than 8.

In yet another aspect the invention resides in the compounds accordingto Formula I selected as described in examples 1-45.

The compounds of Formula I may form salts, which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated.

The compounds of Formula I may contain asymmetric or chiral centers and,therefore, exist in different stereoisomeric forms. It is intended thatall stereoisomeric forms of the compounds of Formula I as well asmixtures thereof, including racemic mixtures, form part of the presentinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example,chromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g. hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of chiral HPLC column.

The skilled artisan will recognize that desirable IC50 values aredependent on the compound tested. For example, a compound with an IC50value less than 10⁻⁵ M is generally considered as a candidate for drugselection. Preferably, this value is lower than 10⁻⁶ M. However, acompound which has a higher IC50 value, but is selective for theparticular receptor, may be even a better candidate.

The compounds of the invention inhibit RORγ activity. Modulation of RORγactivity can be measured using for example biophysical (natural) liganddisplacement studies, biochemical AlphaScreen or FRET assays, cellularGAL4 reporter gene assays, cellular IL-17 promoter reporter assay orfunctional IL-17 ELISA assays using for example mouse splenocytes orhuman peripheral blood mononuclear cells (PBMCs) cultured under T_(H)17polarizing conditions.

In such assays, the interaction of a ligand with RORγ can be determinedby measuring, for example, the ligand modulated interaction ofcofactor-derived peptides with the RORγ ligand binding domain, ormeasuring the gene products of ligand modulated RORγ mediatedtranscription using, for example, luciferase reporter assays or IL-17ELISA assays.

The present invention also relates to a pharmaceutical compositioncomprising compounds or pharmaceutically acceptable salts thereof havingthe general Formula I in admixture with pharmaceutically acceptableexcipients and optionally other therapeutically active agents.

The present invention also relates to a pharmaceutical compositioncomprising compounds or pharmaceutically acceptable salts thereof havingthe general Formula I in admixture with pharmaceutically acceptableexcipients and one or more pharmaceutically acceptable excipients.

The excipients must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The present invention also relates to a pharmaceutical compositioncomprising at least one additional therapeutically active agent.

The invention further includes a compound of Formula I in combinationwith one or more other drug(s).

Compositions include e.g. those suitable for oral, sublingual,subcutaneous, intravenous, intramuscular, nasal, local, or rectaladministration, and the like, all in unit dosage forms foradministration.

For oral administration, the active ingredient may be presented asdiscrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of theinvention may be presented in unit-dose or multi-dose containers, e.g.injection liquids in predetermined amounts, for example in sealed vialsand ampoules, and may also be stored in a freeze dried (lyophilized)condition requiring only the addition of sterile liquid carrier, e.g.water, prior to use.

Mixed with such pharmaceutically acceptable excipients, the active agentmay be compressed into solid dosage units, such as pills, tablets, or beprocessed into capsules or suppositories.

By means of pharmaceutically acceptable liquids the active agent can beapplied as a fluid composition, e.g. as an injection preparation, in theform of a solution, suspension, emulsion, or as a spray, e.g. a nasalspray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable additive, which does notinterfere with the function of the active compounds, can be used.Suitable carriers with which the active agent of the invention can beadministered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration, aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material suitablefor said composition, said packaging material including instructions forthe use of the composition for the use as hereinbefore described.

The exact dose and regimen of administration of the active ingredient,or a pharmaceutical composition thereof, may vary with the particularcompound, the route of administration, and the age and condition of theindividual subject to whom the medicament is to be administered.

In general parenteral administration requires lower dosages than othermethods of administration, which are more dependent upon absorption.However, a dosage for humans preferably contains 0.0001-100 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple sub-doses administered at appropriate intervals throughout theday.

The compounds according to the invention can be used in therapy.

A further aspect of the invention resides in the use of compoundsaccording to the invention or a pharmaceutically acceptable salt thereoffor the treatment of RORγ-mediated diseases or RORγ mediated conditions.

Another aspect of the invention resides in the use of compounds havingthe general Formula I or a pharmaceutically acceptable salt thereof forthe treatment of autoimmune diseases, in particular those diseases inwhich T_(H)17 cells and non-T_(H)17 cells, which express T_(H)17hallmark cytokines play a prominent role. These include, but are notlimited to, the treatment of rheumatoid arthritis, psoriasis,inflammatory bowel disease, Crohn's disease and multiple sclerosis.

In another aspect, compounds having the general Formula I or apharmaceutically acceptable salt thereof can be used for treatment ofinflammatory diseases in which T_(H)17 cells and/or non-T_(H)17 cells,which express T_(H)17 hallmark cytokines play a prominent role such as,but not limited to respiratory diseases, osteoarthritis and asthma.Also, compounds or a pharmaceutically acceptable salt thereof having thegeneral Formula I can be used for treatment of infectious diseases inwhich T_(H)17 cells and/or non-T_(H)17 cells, which express T_(H)17hallmark cytokines play a prominent role such as, but not limited tomucosal leishmaniasis.

Compounds having the general Formula I or a pharmaceutically acceptablesalt thereof can also be used for treatment of other diseases in whichT_(H)17 cells and/or non-T_(H)17 cells, which express T_(H)17 hallmarkcytokines play a prominent role such as, but not limited to Kawaskidisease and Hashimoto's thyroiditis.

In yet another aspect the invention resides in the use of compoundshaving the general Formula I for the treatment of multiple sclerosis,inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoidarthritis, asthma, osteoarthritis, Kawaski disease, Hashimoto'sthyroiditis, cancer and mucosal leishmaniasis.

In another aspect, the compounds according to the invention can be usedin therapies to treat or prevent multiple sclerosis, inflammatory boweldisease, Crohn's disease, psoriasis and rheumatoid arthritis, asthma,osteoarthritis, Kawaski disease, Hashimoto's thyroiditis, cancer andmucosal leishmaniasis.

In another aspect the compounds according to the invention can be usedto treat or prevent psoriasis.

In yet another aspect the compounds according to the invention can beused to treat inflammatory bowel disease.

The invention is illustrated by the following examples.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the invention, the following generalmethods, and other methods known to one skilled in the art, can beapplied to all compounds and subclasses and species of each of thesecompounds, as described herein.

General Methods of Preparation

The compounds described herein, including compounds of general Formula Ican be readily prepared according to the following reaction schemes andexamples, or modifications thereof, using readily available startingmaterials, reagents and conventional synthesis procedures. Many of thereactions can also be carried out under microwave conditions or usingconventional heating or utilizing other technologies such as solid phasereagents/scavengers or flow chemistry. In these reactions, it is alsopossible to make use of variants which are themselves known to thoseskilled in the art, but are not mentioned in greater detail. Forexample, where specific acids, bases, reagents, coupling agents,solvents, etc. are mentioned, it is understood that other suitableacids, bases, reagents, coupling agents, solvents etc. may be used andare included within the scope of the present invention. Furthermore,other methods for preparing compounds of the invention will be readilyapparent to a person of ordinary skill in the art in light of thefollowing reaction schemes and examples. In cases where syntheticintermediates and final products contain potentially reactive functionalgroups, for example amino, hydroxyl, thiol and carboxylic acid groupsthat may interfere with the desired reaction, it may be advantageous toemploy protected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. The compounds obtained by using the generalreaction sequences may be of insufficient purity. The compounds can bepurified by using any of the methods for purification of organiccompounds, for example, crystallization or silica gel or alumina columnchromatography, using different solvents in suitable ratios. Allpossible stereoisomers are envisioned within the scope of the invention.In the discussion below variables have the meaning indicated aboveunless otherwise indicated.

The abbreviations used in these experimental details are listed belowand additional ones should be considered known to a person skilled inthe art of synthetic chemistry.

Abbreviations used herein are as follow: r.t.: room temperature; HATU:2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; DMF: Dimethyl formamide; DiPEA:Diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; DCC:N,N-Dicyclohexylcarbodiimide; mCPBA: 3-chloroperoxybenzoic acid; TFA:Trifluoroacetic acid; THF: Tetrahydrofuran; DMSO: Dimethylsulfoxide;PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; EtOH: Ethanol; EDCI:1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; AIBN:Azobisisobutyronitrile; NBS: N-bromosuccinimide; TBAF:tetra-n-butylammonium fluoride; TMSCN: trimethylsilyl cyanide.

Chemical names are preferred IUPAC names, generated using MarvinSketchversion 6.3.0.

If a chemical compound is referred to using both a chemical structureand a chemical name, and an ambiguity exists between the structure andthe name, the structure predominates.

General Procedures

As depicted in scheme 1, the derivatives of the invention having FormulaI can be prepared by methods known in the art of organic chemistry.Compounds of the invention can for example be obtained by an amidecoupling reaction between a (hetero)aryl acetic acid derivative 1,wherein A₅, A₆, A₇, A₈, R₉, R₁₀ and R₁₁ have the meaning as previouslydescribed, and a (hetero)aryl amino derivative 2, wherein A₁, A₂, A₃,A₄, R₁₂, R₁₃ and R₁₄ have the meaning as previously described, which caneasily be prepared by someone skilled in the art of organic chemistry,using a coupling reagent such as EDCI, HATU, DCC, or PyBOP or the like,in the presence of a suitable base such as DiPEA or catalyst such asDMAP.

In an alternative way, a (hetero)aryl acetic acid derivative 1 can beconverted into an acid chloride, using for example SOCl₂ or oxalylchloride, which then can be coupled, in the presence of a suitable basesuch as Et₃N or the like, with (hetero)aryl amino derivative 2,obtaining derivatives of Formula I.

Alternatively, a (hetero)aryl acetic acid derivative 1 can be condensedwith a suitable acid protected (hetero)aryl amino derivative 3, whereinA₁, A₂, A₃, A₄, and R₁₂ have the meaning as previously described, usingmethods as described above. After removal of the protecting group, theobtained carboxylic acid derivative 4 can be condensed with a suitableamine 5, wherein R₁₃ and R₁₄ have the meaning as previously described,using methods as described before, giving derivatives of Formula I.

Conditions: i) H₂SO₄, EtOH, 60° C.; ii) Alkylhalide, K₂CO₃, CH₃CN, r.t.;iii) mCPBA, CH₂Cl₂, r.t.; iv) 2N NaOH, EtOH, r.t.

Scheme 2 illustrates a general method for preparing2-[4-(alkylsulfonyl)phenyl]acetic acid derivatives of building block 1wherein and R₉, R₁₀, R₁₁, A₅, A₆, A₇ and A₈ have the meaning aspreviously described.

Esterification of 4-mercaptophenylacetic acid derivatives 6 under acidicconditions, using for example H₂SO₄ in ethanol, provides ethyl2-(4-mercaptophenyl)acetate derivatives 7. Alkylation of the sulfurgroup using an alkylhalide in the presence of a base, such as K₂CO₃,gives the corresponding ethyl 2-[4-(alkylsulfanyl)phenyl]acetatederivatives 8. Oxidation, using e.g. mCPBA, gives ethyl2-(4-alkylsulfonylphenyl)acetate derivatives 9 which aftersaponification of the ester moiety under basic conditions, e.g. NaOH inethanol, gives the corresponding 2-[4-(alkylsulfonyl)phenyl]acetic acidderivatives 1.

Conditions (A₆=N): i) Thiourea, HCl (aq), reflux; ii) alkyl halide,K₂CO₃, CH₃CN, r.t.; iii) mCPBA, CH₂Cl₂, 0° C.->RT; iv) NBS, AIBN, CH₃CN,60° C.; v) TMSCN, TBAF, CH₃CN, reflux; vi) NaOH, EtOH, reflux.

Scheme 3 shows a general method for the preparation of2-(6-alkylsulfonylpyridin-3-yl)acetic acid derivatives of building block1 wherein A₆ is N and R₉, R₁₀, R₁₁, A₅, A₇ and A₈ have the meaning aspreviously described.

Reaction of 2-bromo-5-methylpyridine derivatives 10 with thiourea underacidic conditions gives 5-methylpyridine-2-thiol derivatives 11 whichcan be alkylated in the presence of a suitable base such as potassiumcarbonate to give the corresponding 2-(alkylsulfanyl)-5-methylpyridinederivatives 12. Oxidation using mCPBA for example to the correspondingsulfone derivatives 13, which upon radical bromination with NBS inpresence of a radical initiator such as AIBN provides5-(bromomalkyl)-2-(ethylsulfanyl)pyridine derivatives 14. These bromidederivatives can be converted to the corresponding nitrile derivatives 15by treating them with a cyanide source such as TMSCN or potassiumcyanide or the like. If TMSCN is used, it is required to add a fluoridesource such as TBAF or the like to generate the cyanide nucleophile insitu. Hydrolysis of the nitrile derivatives 15 can provide thecorresponding carboxylic acid derivatives of building block 1 wherein A₆is N.

Some of the building blocks 1 are commercially available, known orprepared according to methods known to those skilled in the art.

Conditions: i) Ethanol, HCl_((conc.)), r.t.; ii) a suitable derivative1, EDCI, DMAP, CH₂Cl₂, 60° C.; iii) 2N NaOH, EtOH, reflux; iv) Asuitable amine 5, EDCI, DMAP, CH₂Cl₂, 60° C.

Scheme 4 demonstrates a general method for the preparation of Formula Iamide derivatives wherein R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, A₁, A₂, A₃, A₄,A₅, A₆, A₇ and A₈ have the meaning as previously described.

Reaction of carboxylic acid derivatives 16 with ethanol, under acidicconditions, give the corresponding ethyl ester derivatives 17, which canbe condensed with 2-[4-(alkylsulfonyl)phenyl]acetic acid derivatives 1,in the presence of for example EDCI and DMAP, gives derivatives 18.After saponification of the ester moiety under basic conditions, byusing for example NaOH in ethanol, the obtained derivatives 4 can becondensed with amine derivatives 5, in the presence of for example EDCIand DMAP, giving derivatives of Formula I.

Conditions: i) SOCl₂, CH₂Cl₂, r.t.; ii) A suitable amine 5, triethylamine, CH₂Cl₂, r.t.; iii) A suitable amine 5, EDCI, DMAP, CH₂Cl₂, 60°C.; iv) Zinc powder, NH₄Cl, THF, water 65° C.; v) a suitable derivative1, EDCI, DMAP, CH₂Cl₂, 60° C.

Scheme 5 demonstrates an alternative route for the preparation ofFormula I amide derivatives wherein R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, A₁, A₂,A₃, A₄, A₅, A₆, A₇ and A₈ have the meaning as previously described.

4-Nitrobenzoic acid derivatives 19 can be condensed with suitableamines, in the presence of for example EDCI and DMAP, giving4-nitrobenzamide derivatives 21. Alternatively, 4-nitrobenzoic acidderivatives can easily be converted into the corresponding4-nitrobenzoyl chloride derivatives 20 by using for example SOCl₂ oroxalyl chloride, which then can be coupled with suitable amines in thepresence of a base such as Et₃N or the like.

The nitro group of derivatives 21 can be reduced, by using for exampleNH₄Cl in the presence of zinc or iron, giving the 4-aminobenzamidederivatives 22, which can be condensed with derivatives 1, in thepresence of for example EDCI and DMAP, giving derivatives of Formula Iwherein R₁₂ is hydrogen.

EXAMPLES

All building blocks used are commercially available, known or preparedaccording to methods known to those skilled in the art.

Examples 1-45 1:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide

i) To a solution of N,5-dimethyl-1,2-oxazol-3-amine (0.5 g) and triethylamine (1.9 mL) in CH₂Cl₂ (5 mL) was added 4-nitrobenzoyl chloride (0.91g) in CH₂Cl₂ (5 mL). The reaction mixture was stirred overnight at roomtemperature under a nitrogen atmosphere. The reaction mixture was washedwith water, an aqueous 1M HCl solution, water, a saturated aqueousNaHCO₃ solution, water, brine and dried over MgSO₄. The combined organiclayers were concentrated under reduced pressure and the residue waspurified on SiO₂, using 0% to 6% CH3OH/ethyl acetate (1:1) in CH₂Cl₂ asthe eluent, givingN-methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-nitrobenzamide (824 mg).

ii) To a solution of the product obtained in the previous step (0.82 g)in ethanol (20 mL) was added SnCl₂ (2.99 g). The reaction mixture wasstirred for 1 hour at 70° C. After cooling to room temperature, thereaction mixture was quenched by pouring it onto ice and the pH was setto 14 by addition of an aqueous 2M NaOH solution. The aqueous layer waswashed with ethyl acetate and the combined organic layers were washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure giving 4-amino-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide(687 mg). The product was used in the next step without furtherpurification.

iii) To a solution of the product obtained in the previous step (45 mg),2-[4-(ethanesulfonyl)phenyl]acetic acid (54 mg) and DMAP (5 mg) inCH₂Cl₂ (2 mL) was added dropwise at 0° C. a solution of EDCI (45 mg) inCH₂Cl₂. The reaction mixture was stirred at room temperature overnight.The organic layer was washed with a saturated aqueous NaHCO₃ solution,water then brine, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified on SiO₂, using 1% to 10% methanol inCH₂Cl₂ as the eluent, giving the title compound4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide(42 mg) as a white solid. MS(ES⁺) m/z 442.1 (M+H)⁺.

Following a procedure analogous to that described for example 1, thefollowing compounds have been prepared.

2:N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide

3:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide

4:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide

5:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide

6:N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide

7:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide

8:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-fluoro-N-phenylbenzamide

9:2-chloro-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide

10:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(1,2-oxazol-3-yl)benzamide

11:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide

12:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide

13:N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide

14:N-(dimethyl-1,2-oxazol-4-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide

15:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-methyl-N-phenylbenzamide

16:N-tert-butyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

17:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide

18:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide

19:N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

20:N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

21:N-(3,3-difluorocyclobutyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide

22:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

23:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(pyridin-2-yl)benzamide

i) To a suspension of 4-aminobenzoic acid (20 g) in methanol (150 mL)was added concentrated HCl (25 mL) and the resulting mixture was stirredovernight at room temperature. The reaction mixture was quenched by theaddition of a saturated aqueous NaHCO₃ solution. The organic solvent wasremoved under reduced pressure and the aqueous layer was extracted withethyl acetate. The combined organic phases were washed water, brine,dried over MgSO₄ and concentrated under reduced pressure giving methyl4-aminobenzoate as an off white solid (20 g). The product was used inthe next step without further purification.

ii) Following a procedure analogous to that described in example 1, stepiii, using the product obtained in the previous step (390 mg) and2-[4-(ethanesulfonyl)phenyl]acetic acid (500 mg) as the startingmaterials, methyl 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoate (560mg) has been synthesized.

iii) To a solution of the product obtained in the previous step (560 mg)in ethanol was added a aqueous 2N NaOH solution (5 mL) and the resultingmixture was stirred overnight at room temperature. After adding water(100 mL) the mixture was washed with CH₂Cl₂ and acidified to pH=6 byaddition of an aqueous 6M HCl solution. The precipitate was filteredoff, washed with water and dried at 40° C. under reduced pressure. Theobtained 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoic acid (390 mg)was used in the next step without further purification.

iv) Following a procedure analogous to that described in example 1, stepiii, using the product obtained in the previous step (40 mg) and2-(methylamino)pyridine (15 mg) as the starting materials, methyl4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzoate (19 mg) wassynthesized. MS(ES⁺) m/z 438.2 [M+H]⁺.

Following a procedure analogous to that described for example 23, thefollowing compounds have been prepared.

24:6-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide

25: N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide

26: N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methylbenzamide

27:N-(cyclopropylmethyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide

28:2-[4-(ethanesulfonyl)phenyl]-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide

29:2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide

30: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide

31:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide

32:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide

33:2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide

34: 4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide.

35: N, N-dicyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide

36:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide

37:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(furan-2-ylmethyl)-N-methylbenzamide

38: N,N-dibenzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide

39:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide

40:N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide

41:N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide

42:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide

i) Following a procedure analogous to that described for example 1,using appropriate starting materials,N-{1-[(tert-butyldiphenylsilyl)oxy]-2-methylpropan-2-yl}-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)benzamidehas been prepared.

ii) A suspension of the product obtained in the previous step (82 mg)and NH₄F (41 mg) in methanol (20 mL) was stirred overnight at 60° C. Thereaction mixture was concentrated under vacuo and the residue wasdissolved in ethyl acetate. This solution was washed with water, brine,dried over magnesium sulfate and concentrated under reduced vacuo. Theresidue was purified on reverse phase HPLC, giving the title compound4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide(10 mg). MS(ES⁺) m/z 509.2 (M+H)⁺.

43:4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide

i) To a suspension of 2-bromo-5-methylpyridine (10 g) in water (70 ml)was added at room temperature an aqueous 25% HCl solution, after whichthiourea (9.6) was added until the reaction mixture became a clearsolution. The reaction mixture was stirred at reflux temperature for 48hours during which more thiourea (7.3 g) was added portion wise, untilcomplete conversion. The reaction mixture was cooled to 0° C. andquenched by the addition of an aqueous 4N NaOH solution (51 ml). Theformed precipitate was dissolved in CH₂Cl₂ (200 mL) and the organiclayer was washed with water. The aqueous layer was acidified to pH=3 andextracted with CH₂Cl₂ 3 times. The combined organic layers were driedover MgSO₄ and concentrated under vacuo. The residue was recrystallizedfrom ethanol to give 5-methylpyridine-2-thiol (4.5 g) as a white solid.

ii) To a suspension of the product obtained in the previous step (2.3 g)and K₂CO₃ (600 mg) in acetonitrile (45 mL) was added at room temperaturebromoethane (1.7 mL). After stirring for 17 hours, the reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.The crude product (2.8 g) was purified via an acid-base extraction. Theorganic layer was dried on MgSO₄ and concentrated under reduced pressureto give 2-(ethylsulfanyl)-5-methylpyridine (2.6 g)

iii) m-CPBA (8.9 g) was added to an ice cold solution of the productobtained in the previous step (2.6 g) in CH₂Cl₂ (75 mL). After stirringthe reaction mixture over the weekend at room temperature, the reactionmixture was filtered and the filtrate was washed with a saturatedaqueous NaHCO₃ solution, water and brine. The organic layer was dried onMgSO₄ and concentrated under reduced pressure. The crude product waspurified on SiO₂, using 0% to 50% ethyl acetate in heptane as the eluentto give 2-(ethanesulfonyl)-5-methylpyridine (2.0 g) as a white solid.

iv) To a solution of the product obtained in the previous step (990 mg)in acetonitrile (25 mL) were added NBS (950 mg) and AIBN (44 mg). Thereaction mixture was stirred for 17 hours at reflux temperature under anitrogen atmosphere. After cooling, the reaction mixture was filteredand the filtrate was concentrated under reduced pressure. The crudeproduct was purified on SiO₂, using 0% to 50% ethyl acetate in heptaneas the eluent, to give 5-(bromomethyl)-2-(ethanesulfonyl)pyridine (817mg).

v) The product obtained in the previous step (684 mg) was added to anitrogen purged solution of trimethylsilyl cyanide (486 uL) and TBAF(3375 uL) in acetonitrile (25 mL). The reaction mixture was stirred at85° C. in a microwave reactor for 4 hours. After cooling to roomtemperature the reaction mixture was diluted with a 3 to 1 mixture ofCH₂Cl₂ and 2-propanol. The resulting mixture was washed with water,brine, dried on MgSO₄, filtered and the filtrate was concentrated underreduced pressure. The crude product was purified on SiO₂, using 0% to70% ethyl acetate in heptane as the eluent to give2-[6-(ethanesulfonyl)pyridin-3-yl]acetonitrile (315 mg) as a whitesolid.

vi) To a solution of the product obtained in the previous step (315 mg)in ethanol (3 mL) was added a 2N aqueous NaOH solution. The reactionmixture was stirred for 2 hours in a microwave reactor at 100° C. Aftercooling to room temperature, the reaction mixture was washed withCH₂Cl₂. The aqueous layer was acidified to pH=3 and extracted with ethylacetate. The combined organic layers were washed with water, brine,dried on MgSO₄, filtered and concentrated under reduced pressure to give2-[6-(ethanesulfonyl)pyridin-3-yl]acetic acid as the crude product. Theproduct was used in the next step without further purification.

vii) Following a procedure analogous to that described for example 1,using the product obtained in the previous step and appropriate startingmaterials, the title compound4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide(61 mg) has been prepared. MS(ES⁺) m/z 470.2 (M+H)⁺.

Following a procedure analogous to that described for example 43, thefollowing compounds have been prepared.

44:N-tert-butyl-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-phenylbenzamide

45:2-chloro-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-N-phenylbenzamide

Example 46

RORγ GAL4 Reporter Gene Assay

Example inhibitors 1-45 were tested for their ability to inhibit RORγactivity in a RORγ GAL4 reporter gene assay. The assay procedure andresults are described below.

RORγ GAL4 Reporter Gene Assay Description

A GAL4 one-hybrid reporter system employing luciferase readout wasestablished to determine inhibition of RORγ in 293FT cells. The RORγligand-binding domain (LBD) was fused to the yeast GAL4 DNA bindingdomain (DBD) and placed under the control of the human cytomegalovirus(CMV) immediate early promoter, using expression vector pFN26A (Promega)and standard recombinant DNA cloning methods. To serve as a control inthe assay, a similar vector was generated in which the GAL4-DBD wasfused to Herpes simplex virus protein 16 (VP16), a constitutivetranscriptional activator.

To monitor the inhibitory effect of compounds on RORγ, a transcriptionalreporter construct was used. The pGL4.35 vector (Promega) contains ninecopies of the GAL4 Upstream Activator Sequence (UAS). This sequencedrives the transcription of the luciferase reporter gene luc2P inresponse to binding of a fusion protein containing the GAL4 DNA bindingdomain, as for example expressed by the GAL4-RORγ-LBD and GAL4-VP16expression vectors described above. To allow a GAL4 fusion protein todrive the expression of the luciferase reporter, the pGL4.35 expressionvector and the appropriate GAL4 fusion protein expression vector werebulk transfected in the 293FT cells using standard transfectiontechniques.

The day after transfection, cells were plated into 96 well plates, testcompound was added and the plates were incubated overnight.Subsequently, the firefly luciferase activity was quantified usingluciferase detection reagent and luminescence readout.

Detailed Assay Description

293FT cells (Invitrogen) were transfected with a GAL4 fusion proteinexpression vector (as described above) and the transcriptional reporterconstruct (pGL4.35, Promega). 60 μL of TransIT-293 transfection reagent(Mirus Bio) was added drop wise to 1500 μl Opti-MEM I Reduced SerumMedium (Invitrogen) and incubated at room temperature (RT) for 5 to 20minutes. 1500 μL of this reagent mixture was added to 5 μg of GAL4fusion protein expression vector and 5 μg of the transcriptionalreporter construct, and incubated at RT for 20 minutes.

To harvest 293FT cells from a T75 flask, first the culture medium wastaken off the cells. Subsequently, the cells were washed with PhosphateBuffered Saline (PBS) (Lonza), after which the PBS was removed. Todissociate the cells, 1 ml of TrypLE Express (Invitrogen) was added tothe flask, followed by incubation at RT until the cells visually startedto detach. Cells were collected in 5 mL of assay medium (DMEM culturemedium (Lonza), 10% dialyzed FBS (Invitrogen) and Pen/Strep (Lonza)) toachieve a single cell suspension. 10×10⁶ cells were spun down andre-suspended in 10 mL of assay medium. Subsequently, the cell suspensionwas added to the transfection mix tube, and then transferred as a wholeto a T75 flask (Greiner), followed by overnight (16-24 hours) incubationat 37° C. and 5% CO₂.

For compound screening, the cells were harvested (as described above)and counted. 13×10⁶ cells were spun down, the supernatant was aspiratedand the cells were re-suspended in 17.3 mL of assay medium obtaining acell suspension of 0.75×10⁶ cells/mL. 80 μL of cell suspension (60,000cells) was plated per well into a white, flat bottom, tissue culturetreated, 96 well screening plates (Greiner).

Test compounds were diluted, starting from a 10 mM DMSO stock solution,to serial dilutions in DMSO at 500× the final test concentration.Subsequently, these solutions were diluted to 5× the final testconcentration in two 10-fold-dilution steps in assay medium. The finalDMSO concentration of the 5× test compound solution was 1%. 20 μL of the5× test compound solution was added to each test well of the 96 wellplate previously plated with 80 μl cell suspension, resulting in thefinal test concentration with 0.2% DMSO.

The plates were incubated overnight (16-24 hours) at 37° C. and 5% CO₂.

For the luciferase readout, the luciferase reagent (Britelite Plus,Perkin Elmer) was brought to RT. To each test well of the screeningplates, 100 μL of 2.5-fold diluted Britelite Plus reagent was added,followed by incubation at RT for 10 minutes. The luciferase luminescencesignal was measured using a Wallac Victor Microplate Reader (PerkinElmer).

The half maximum inhibitory concentration (IC₅₀) values for the testcompounds were calculated from the luciferase signal using GraphPadPrism software (GraphPad Software).

All exemplified compounds of Formula I (Examples 1-45) were found tohave mean pIC₅₀ values above 5.

Examples 1-22, 23-35, 37, 38 and examples 40-44 were found to have meanpIC₅₀ values above or equal to 6.

Examples 2, 3, 5, 6, 7-9, 11, 13, 16-22, 25, 28, 30, 31, 33, 34, 38, 42and 44 were found to have mean pIC₅₀ values above or equal to 7.

Examples 11, 13, 16, 18 and 34 were found to have mean pIC₅₀ valuesabove or equal to 8.

Example 47

Peripheral Blood Mononuclear Cell (PBMC) IL-17 Assay

Example inhibitors 2, 5, 6, 11, 13, 16, 17, 18, 21 and 44 were testedfor their ability to inhibit the IL-17A production in anti-CD3/anti-CD28stimulated peripheral blood mononuclear cells (PBMCs) isolated fromhuman blood. The assay procedure and results are described below.

PBMC IL-17 Assay Description

This assay is designed to measure the levels of IL-17A secreted fromanti-CD3/anti-CD28 stimulated PBMCs with the aim of measuring RORγmediated inhibition of IL-17A production.

The assay medium consists of 90% RPMI 1640 (Lonza), 10% heat inactivatedfetal bovin serum (FBS, Lonza) and 100 U/mL penicillin/streptomycinsolution.

Assay Description

Anti-CD3 antibody (BD Pharmingen) was diluted to 10 μg/ml in PBS(Lonza). 30 μL of 10 μg/ml anti-CD3 solution was added to the inner 60wells, excluding any negative control wells, of a 96-well cell culturetreated U-bottom plate (Greiner). Plates were incubated overnight (16-24hours) at 37° C. and 5% CO₂.

Peripheral blood mononuclear cells were separated from buffy coats(Sanquin) using Ficoll-Paque PREMIUM separation medium (GE HealthcareLife Sciences) according to manufacturer's protocol and re-suspended inassay medium at 37° C.

Test compounds were diluted, starting from a 10 mM dimethylsulfoxide(DMSO) stock solution, to serial dilutions in DMSO at 200× the finaltest concentration. Subsequently, these solutions were diluted in twodilution steps in assay medium to 10× the final test concentration. TheDMSO concentration of the 10× test compound solution was 5%.

Anti-CD28 antibody (BD Pharmingen) was diluted to 20 μg/mL in PBS. ThePBMCs were diluted to a concentration of 2.5×10⁶ cells/mL in assaymedium at 37° C.

For compound screening, the anti-CD3 coated plates were washed threetimes with PBS, the wells were subsequently aspirated using vacuum. Toeach screening well 80 μL of the PBMC suspension, 10 μL of the anti-CD28solution and 10 μL of the 1 Ox test compound solution was added,resulting in the final test concentration with 0.5% DMSO. All outerwells were filled with assay medium to prevent evaporation. Plates wereincubated for 5 days at 37° C. and 5% CO₂.

After incubation the plates were spun down at 1500 rpm for 4 minutes andthe supernatant was collected. Subsequently, the IL-17A levels in thesupernatants was determined using an IL-17 ELISA kit (human IL-17DuoSet, R&D systems) according to manufacturer's protocol.

The half maximum inhibitory concentration (IC₅₀) values for the testcompounds were calculated from the IL-17A signal using GraphPad Prismsoftware (GraphPad Software).

The tested examples 2, 5, 6, 11, 13, 16, 17, 18, 21 and 44 were found tohave mean pIC₅₀ values above or equal to 7.

The tested examples 11 and 16 were found to have mean pIC50 values aboveor equal to 8.

The invention claimed is:
 1. A compound according to Formula I

or a pharmaceutically acceptable salt thereof wherein: A₁-A₈ areCR₁-CR₈; R₁-R₈ are independently H, halogen, amino, C(1-3)alkoxy,(di)C(1-3)alkylamino or C(1-6)alkyl; R₉ is C(1-6)alkyl; R₁₀ and R₁₁ areindependently H, F, methyl, ethyl, hydroxy or methoxy or R₁₀ and R₁₁together is carbonyl, all alkyl groups, if present, optionally beingsubstituted with one or more F; R₁₂ is H or C(1-6)alkyl; R₁₃ isC(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl,C(2-5)heterocycloalkylC(1-3)alkyl, C(6- 10)aryl, C(6-10)arylC(1-3)alkyl,C(1-9)hetero-aryl or C(1-9)heteroarylC(1-3)alkyl, all groups optionallysubstituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;R₁₄ is H, C(1-6)alkyl, C(2-6)alkenyl, C(3-6)cycloalkyl,C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl,C(2-5)heterocycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl,C(1-9)heteroaryl or C(1-9)heteroarylC(1-3)alkyl, all groups optionallysubstituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;or R₁₃ and R₁₄ are fused and form a ring having 5 to 7 atoms by joiningR₁₃ being C(1-6)alkyl or C(2-6)alkenyl with an independent substituentwithin the definition of R₁₄, all groups optionally substituted with oneor more halogen, amino, hydroxy, cyano, C(1-3)alkoxy,C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl; the termC(1-9)heteroaryl denotes an aromatic group having 1-9 carbon atoms and1-4 heteroatoms, which is attached via a nitrogen atom or a carbon atom,and all carbon atoms of the aromatic group may optionally be substitutedwith one or more halogen or methyl; the term C(2-5)heterocycloalkyldenotes a saturated cyclic hydrocarbon group having 2-5 carbon atoms and1-3 heteroatoms, which is attached via a nitrogen atom or a carbon atom,and all carbon atoms of the saturated cyclic hydrocarbon group mayoptionally be substituted with one or more halogen or methyl; and theterm heteroatom denotes a nitrogen, sulfur or oxygen atom.
 2. Thecompound according to claim 1, wherein R₁-R₈ are independently H,halogen or methyl.
 3. The compound according to claim 1, wherein R₉ isC(1-3)alkyl.
 4. The compound according to claim 1, wherein R₁₀ and R₁₁are both H.
 5. The compound according to claim 1, wherein R₁₂ is H. 6.The compound according to claim 1, wherein R₁₃ is C(3-6)cycloalkyl,C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl,C(4)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl,C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, all groups optionallysubstituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl.7. The compound according to claim 1, wherein R₁₄ is H, C(1-6)alkyl,C(2-6)alkenyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl,C(4)heterocycloalkyl, C(2-5)heterocycloalkylC(1-3)alkyl, C(6)aryl,C(6)arylC(1-3)alkyl, C(1-5)heteroaryl or C(1-5)heteroarylC(1-3)alkyl,all groups optionally substituted with one or more halogen, amino,hydroxy, cyano, C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylaminoor C(1-3)alkyl; and the term C(1-5)heteroaryl denotes an aromatic grouphaving 1-5 carbon atoms and 1-4 heteroatoms, which is attached via anitrogen atom or a carbon atom, and all carbon atoms in the aromaticgroup may optionally be substituted with one or more halogen or methyl.8. The compound according to claim 1, wherein R₁₃ and R₁₄ are fused andform a ring having 5 to 7 atoms by joining R₁₃ being C(1-6)alkyl orC(2-6)alkenyl with an independent R₁₄ substituent selected fromC(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl,C(2-5)heterocycloalkyl-C(1-3)alkyl, C(6)aryl, C(6)arylC(1-3)alkyl,C(1-5)heteroaryl or C(1-5)heteroaryl-C(1-3)alkyl, all groups optionallysubstituted with one or more halogen, amino, hydroxy, cyano,C(1-3)alkoxy, C(1-3)alkoxycarbonyl, (di)C(1-3)alkylamino or C(1-3)alkyl;and the term C(1-5)heteroaryl denotes an aromatic group having 1-5carbon atoms and 1-4 heteroatoms, which is attached via a nitrogen atomor a carbon atom, and all carbon atoms of the aromatic group mayoptionally be substituted with one or more halogen or methyl.
 9. Thecompound selected from claim 1, which is selected from the group of:4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(5-methyl-1,2-oxazol-3-yl)benzamide;N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(3-methyl-1,2-oxazol-5-yl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(5-methyl-1,2-oxazol-3-yl)-N-propylbenzamide;N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-fluoro-N-phenylbenzamide;2chloro-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(1,2-oxazol-3-yl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(2,2,2-trifluoroethyl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-3-methyl-N-phenylbenzamide;N-(4-methyl-5-methyl-1,3-thiazol-2-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;N-(dimethyl-1,2-oxazol-4-yl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-2-methyl-N-phenylbenzamide;N-tert-butyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(4-methylphenyl)-N-[2-(oxolan-2-yl)propan-2-yl]benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-[2-(oxolan-2-yl)propan-2-yl]-N-phenylbenzamide;N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;N-(3,3-difluorocyclobutyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-phenyl-N-(1,1,1-trifluoropropan-2-yl)benzamide4-{2[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-(pyridin-2-yl)benzamide;6-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylpyridine-3-carboxamide;N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;N-benzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methylbenzamide;N-(cyclopropylmethyl)-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propylbenzamide;2-[4-(ethanesulfonyl)phenyl]-N-[4-(1,2,3,4-tetrahydroquinoline-1-carbonyl)phenyl]acetamide;2-[4(ethanesulfonyl)phenyl]-N-[4-(2-phenylpyrrolidine-1-carbonyl)phenyl]acetamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-methyl-N-phenylbenzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-propyl-N-(pyridin-3-yl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-(pyridin-3-yl)benzamide;2-[4-(ethanesulfonyl)phenyl]-N-[4-(2-phenylpiperidine-1-carbonyl)phenyl]acetamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-phenylbenzamide;N,N-dicyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-ethyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(furan-2-ylmethyl)-N-methylbenzamide;N,N-dibenzyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(oxolan-3-yl)-N-(pyridin-2-yl)benzamide;N-cyclopropyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide;N-cyclobutyl-4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(pyridin-2-yl)benzamide;4-{2-[4-(ethanesulfonyl)phenyl]acetamido}-N-(1-hydroxy-2-methylpropan-2-yl)-N-(4-methylphenyl)benzamide;4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-2-fluoro-N-phenylbenzamide;N-tert-butyl-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-phenylbenzamide;and2-chloro-4-{2-[6-(ethanesulfonyl)pyridin-3-yl]acetamido}-N-ethyl-N-phenylbenzamide.10. A pharmaceutical composition that comprises a compound of Formula Iaccording to claim 1 or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable excipients.